Dennis Mah

Physico-Chemical Evaluation of Rationally Designed Melanins as Novel Nature-Inspired Radioprotectors

Background Melanin, a high-molecular weight pigment that is ubiquitous in nature, protects melanized microorganisms against high doses of ionizing radiation. However, the physics of melanin interaction with ionizing radiation is unknown. Methodology/Principal Findings We rationally designed melanins from either 5-S-cysteinyl-DOPA, L-cysteine/L-DOPA, or L-DOPA with diverse structures as shown by elemental analysis and HPLC. Sulfur-containing melanins had higher predicted attenuation coefficients than non-sulfur-containing melanins. All synthetic melanins displayed strong electron paramagnetic resonance (2.14·1018, 7.09·1018, and 9.05·1017 spins/g, respectively), with sulfur-containing melanins demonstrating more complex spectra and higher numbers of stable free radicals. There was no change in the quality or quantity of the stable free radicals after high-dose (30,000 cGy), high-energy (137Cs, 661.6 keV) irradiation, indicating a high degree of radical stability as well as a robust resistance to the ionizing effects of gamma irradiation. The rationally designed melanins protected mammalian cells against ionizing radiation of different energies. Conclusions/Significance We propose that due to melanins numerous aromatic oligomers containing multiple π-electron system, a generated Compton recoil electron gradually loses energy while passing through the pigment, until its energy is sufficiently low that it can be trapped by stable free radicals present in the pigment. Controlled dissipation of high-energy recoil electrons by melanin prevents secondary ionizations and the generation of damaging free radical species.

Point vs. volumetric bladder and rectal doses in combined intracavitary-interstitial high-dose-rate brachytherapy: Correlation and comparison with published Vienna applicator data

PURPOSE We correlated rectal and bladder point and volumetric dose data in patients treated for advanced cervix cancers with combined intracavitary-interstitial high-dose-rate (HDR) brachytherapy (BT). The results are compared with published Vienna applicator data. METHODS AND MATERIALS We retrospectively analyzed 30 individual combined intracavitary plus interstitial implants from 10 patients treated with external beam radiation therapy (EBRT) followed by HDR BT for locally advanced cervix carcinoma. EBRT consisted of 45 Gy to the pelvis followed by 9-14.4 Gy boost to involved parametria. BT consisted of a total dose of 21 Gy delivered in 7 Gy fraction. For each implant, CT-image-based simulation and image-guided BT treatment planning was performed. Bladder and rectal doses were evaluated and analyzed using both International commission on Radiation Units and Measurements (ICRU) reference points and dose-volume histograms. The cumulative doses to the rectum and bladder were calculated by combining contributions from external beam therapy and BT. To facilitate comparison with published literature, the total doses were normalized to equivalent dose in 2-Gy fractions (EQD2) using the equation EQD2total = EQD2EBRT + EQD2BT. RESULTS For the patient population considered, the mean ICRU bladder dose was 75 (+/-4) Gy3 compared to bladder D0.1 cc and D2 cc doses of 84 (+/-4) and 78 (+/-3) Gy3, respectively. The mean ICRU rectal dose was 73 (+/-4) Gy3 compared to rectal D0.1 cc and D2 cc doses of 79 (+/-5) and 74 (+/-4) Gy3, respectively. For rectum, the mean dose ratios (D0.1 cc/D(ICRU)) and (D2 cc/D(ICRU)) were 1.08 and 1.01, respectively, compared to Vienna applicator study mean dose ratios of 1.08 and 0.93, respectively. ICRU rectal dose correlated with volumetric rectal doses and best with volumetric D2 cc dose (rS = 0.91, p = 0.0003); however, ICRU bladder dose did not correlate with volumetric bladder dose. CONCLUSIONS Our study findings reveal a strong correlation between ICRU rectal reference dose and volumetric rectal D2 cc dose in combined intracavitary-interstitial HDR brachytherapy. This surrogate rectal-dose relationship is valuable in establishing rectal tolerance dose levels in transitioning from traditional two-dimensional to image-based three-dimensional dose planning.

Image guidance in radiation oncology treatment planning: the role of imaging technologies on the planning process.

Radiation therapy has evolved from 2-dimensional (2D) to 3-dimensional (3D) treatments and, more recently, to intensity-modulated radiation therapy and image-guided radiation therapy. Improvements in imaging have enabled improvements in targeting and treatment. As computer-processing power has improved during the past few decades, it has facilitated developments in both imaging and treatment. The historical role of imaging from 2D to image-guided radiation therapy is reviewed here. Examples of imaging technologies such as positron emission tomography and magnetic resonance imaging are provided. The role of these imaging technologies, organ motion management approaches and their potential impacts on radiation therapy are described.

Clinical experiences with onboard imager KV images for linear accelerator-based stereotactic radiosurgery and radiotherapy setup.

PURPOSE To report our clinical experiences with on-board imager (OBI) kV image verification for cranial stereotactic radiosurgery (SRS) and radiotherapy (SRT) treatments. METHODS AND MATERIALS Between January 2007 and May 2008, 42 patients (57 lesions) were treated with SRS with head frame immobilization and 13 patients (14 lesions) were treated with SRT with face mask immobilization at our institution. No margin was added to the gross tumor for SRS patients, and a 3-mm three-dimensional margin was added to the gross tumor to create the planning target volume for SRT patients. After localizing the patient with stereotactic target positioner (TaPo), orthogonal kV images using OBI were taken and fused to planning digital reconstructed radiographs. Suggested couch shifts in vertical, longitudinal, and lateral directions were recorded. kV images were also taken immediately after treatment for 21 SRS patients and on a weekly basis for 6 SRT patients to assess any intrafraction changes. RESULTS For SRS patients, 57 pretreatment kV images were evaluated and the suggested shifts were all within 1 mm in any direction (i.e., within the accuracy of image fusion). For SRT patients, the suggested shifts were out of the 3-mm tolerance for 31 of 309 setups. Intrafraction motions were detected in 3 SRT patients. CONCLUSIONS kV imaging provided a useful tool for SRS or SRT setups. For SRS setup with head frame, it provides radiographic confirmation of localization using the stereotactic target positioner. For SRT with mask, a 3-mm margin is adequate and feasible for routine setup when TaPo is combined with kV imaging.

ICRU reference dose in an era of intensity-modulated radiation therapy clinical trials: correlation with planning target volume mean dose and suitability for intensity-modulated radiation therapy dose prescription.

BACKGROUND AND PURPOSE IMRT clinical trials lack dose prescription and specification standards similar to ICRU standards for two- and three-dimensional external beam planning. In this study, we analyzed dose distributions for patients whose treatment plans incorporated IMRT, and compared the dose determined at the ICRU reference point to the PTV doses determined from dose-volume histograms. Additionally, we evaluated if ICRU reference type single-point dose prescriptions are suitable for IMRT dose prescriptions. MATERIALS AND METHODS For this study, IMRT plans of 117 patients treated at our institution were randomly selected and analyzed. The treatment plans were clinically applied to the following disease sites: abdominal (11), anal (10), brain (11), gynecological (15), head and neck (25), lung (15), male pelvis (10) and prostate (20). The ICRU reference point was located in each treatment plan following ICRU Report 50 guidelines. The reference point was placed in the central part of the PTV and at or near the isocenter. In each case, the dose was calculated and recorded to this point. For each patient--volume and dose (PTV, PTV mean, median and modal) information was extracted from the planned dose-volume histogram. RESULTS The ICRU reference dose vs PTV mean dose relationship in IMRT exhibited a weak positive association (Pearson correlation coefficient 0.63). In approximately 65% of the cases studied, dose at the ICRU reference point was greater than the corresponding PTV mean dose. The dose difference between ICRU reference and PTV mean doses was 2% in approximately 79% of the cases studied (average 1.21% (+/-1.55), range -4% to +4%). Paired t-test analyses showed that the ICRU reference doses and PTV median doses were statistically similar (p=0.42). The magnitude of PTV did not influence the difference between ICRU reference and PTV mean doses. CONCLUSIONS The general relationship between ICRU reference and PTV mean doses in IMRT is similar to that in 3D CRT distributions. Point doses in IMRT are influenced by the degree of intensity modulation as well as calculation grid size utilized. Although the ICRU reference point type prescriptions conceptually may be extended for IMRT dose prescriptions and used as a representative of tumor dose, new universally acceptable dose prescription and specification standards for IMRT based on RTOG IMRT prescription model incorporating dose-volume specification would likely lead to greater consistency among treatment centers.

Application of AAPM TG 119 to volumetric arc therapy (VMAT)

The purpose of this study was to create AAPM TG 119 benchmark plans for volumetric arc therapy (VMAT) and to compare VMAT plans with IMRT plan data. AAPM TG 119 proposes a set of test clinical cases for testing the accuracy of IMRT planning and delivery system. For these test cases, we generated two treatment plans, the first plan using 7–9 static dMLC IMRT fields and a second plan utilizing one‐ or two‐arc VMAT technique. Dose optimization and calculations performed using 6 MV photons and Eclipse treatment planning system. Dose prescription and planning objectives were set according to the TG 119 goals. Plans were scored based on TG 119 planning objectives. Treatment plans were compared using conformity index (CI) for reference dose and homogeneity index (HI) (for D5‐D95). F or test cases prostate, head‐and‐neck, C‐shape and multitarget prescription dose are 75.6 Gy, 50.4 Gy, 50 Gy and 50 Gy, respectively. VMAT dose distributions were comparable to dMLC IMRT plans. Our planning results matched TG 119 planning results. For treatment plans studied, conformity indices ranged from 1.05–1.23 (IMRT) and 1.04–1.23 (VMAT). Homogeneity indices ranged from 4.6%–11.0% (IMRT) and 4.6%–10.5% (VMAT). The ratio of total monitor units necessary for dMLC IMRT to that of VMAT was in the range of 1.1–2.0. AAPM TG 119 test cases are useful to generate VMAT benchmark plans. At preclinical implementation stage, plan comparison of VMAT and IMRT plans of AAPM TG 119 test case allowed us to understand basic capabilities of VMAT technique. PACS number: 87.55.Qr

Novel lung IMRT planning algorithms with nonuniform dose delivery strategy to account for respiratory motion.

To effectively deliver radiation dose to lung tumors, respiratory motion has to be considered in treatment planning. In this paper we first present a new lung IMRT planning algorithm, referred as the dose shaping (DS) method, that shapes the dose distribution according to the probability distribution of the tumor over the breathing cycle to account for respiratory motion. In IMRT planning a dose-based convolution method was generally adopted to compensate for random organ motion by performing 4-D dose calculations using a tumor motion probability density function. We modified the CON-DOSE method to a dose volume histogram based convolution method (CON-DVH) that allows nonuniform dose distribution to account for respiratory motion. We implemented the two new planning algorithms on an in-house IMRT planning system that uses the Eclipse (Varian, Palo Alto, CA) planning workstation as the dose calculation engine. The new algorithms were compared with (1) the conventional margin extension approach in which margin is generated based on the extreme positions of the tumor, (2) the dose-based convolution method, and (3) gating with 3 mm residual motion. Dose volume histogram, tumor control probability, normal tissue complication probability, and mean lung dose were calculated and used to evaluate the relative performance of these approaches at the end-exhale phase of the respiratory cycle. We recruited six patients in our treatment planning study. The study demonstrated that the two new methods could significantly reduce the ipsilateral normal lung dose and outperformed the margin extension method and the dose-based convolution method. Compared with the gated approach that has the best performance in the low dose region, the two methods we proposed have similar potential to escalate tumor dose, but could be more efficient because dose is delivered continuously.

Use of proton beams with breast prostheses and tissue expanders

Since the early 2000s, a small but rapidly increasing number of patients with breast cancer have been treated with proton beams. Some of these patients have had breast prostheses or tissue expanders in place during their courses of treatment. Procedures must be implemented to plan the treatments of these patients. The density, kilovoltage x-ray computed tomography numbers (kVXCTNs), and proton relative linear stopping powers (pRLSPs) were calculated and measured for several test sample devices. The calculated and measured kVXCTNs of saline were 1% and 2.4% higher than the values for distilled water while the calculated RLSP for saline was within 0.2% of the value for distilled water. The measured kVXCTN and pRLSP of the silicone filling material for the test samples were approximately 1120 and 0.935, respectively. The conversion of kVXCTNs to pRLSPs by the treatment planning system standard tissue conversion function is adequate for saline-filled devices but for silicone-filled devices manual reassignment of the pRLSPs is required.

Dose Sparing of Brainstem and Spinal Cord for Re-Irradiating Recurrent Head and Neck Cancer with Intensity-Modulated Radiotherapy

Because of the dose limit for critical structures such as brainstem and spinal cord, administering a dose of 60 Gy to patients with recurrent head and neck cancer is challenging for those who received a previous dose of 60-70 Gy. Specifically, previously irradiated head and neck patients may have received doses close to the tolerance limit to their brainstem and spinal cord. In this study, a reproducible intensity-modulated radiation therapy (IMRT) treatment design is presented to spare the doses to brainstem and spinal cord, with no compromise of prescribed dose delivery. Between July and November 2008, 7 patients with previously irradiated, recurrent head and neck cancers were treated with IMRT. The jaws of each field were set fixed with the goal of shielding the brainstem and spinal cord at the sacrifice of partial coverage of the planning target volume (PTV) from any particular beam orientation. Beam geometry was arranged to have sufficient coverage of the PTV and ensure that the constraints of spinal cord <10 Gy and brainstem <15 Gy were met. The mean maximum dose to the brainstem was 12.1 Gy (range 6.1-17.3 Gy), and the corresponding mean maximum dose to spinal cord was 10.4 Gy (range 8.2-14.1 Gy). For most cases, 97% of the PTV volume was fully covered by the 95% isodose volume. We found empirically that if the angle of cervical spine curvature (Cobbs angle) was less than ∼30°, patients could be treated by 18 fields. Six patients met these criteria and were treated in 25 minutes per fraction. One patient exceeded a 30° Cobbs angle and was treated by 31 fields in 45 minutes per fraction. We have demonstrated a new technique for retreatment of head and neck cancers. The angle of cervical spine curvature plays an important role in the efficiency and effectiveness of our approach.

SU‐E‐T‐618: Flattening Filter Free Beams for 3D Breast Planning

Purpose: To establish the characteristics of flattening filter free (FFF) beams for 3D breast treatments. Methods: FFF beams have an approximate Gaussian shaped intensity distribution as does the breast contour. We produced 3D plans using a half‐beam block technique that combined 15X, 10X, 6X flattened beams and 6X and 10X FFF beams. One year of breast patient plans were retrospectively analyzed (48 supine, 57 prone). Of these, 12 representative shapes of typical and extreme separations were evaluated. The effects of breast separation and breast thickness‐ taken as an orthogonal between the nipple region and the chest wall and breast shape‐ approximated by the ratio of the first two parameters, were used as selection criteria. Our goals were to ensure Dmax< 110% and that the 95% isodose line covered the breast volume. Comparisons were made on the central axis between a FFF beam and a wedged beam to determine the effective wedge angle of an FFF beam. Results: Most supine patients met the coverage goals in the breast tissue, but there are cold areas in the superior margin and the inferior margin. In both these regions, the breast shape is approximately constant, while the FFF beam intensity continues to decrease. Prone patients produced acceptable distributions since gravity pulled the target volume away from the chest wall. The effective wedge angle for 6X and 10X beam were 30–45 and 60 degrees respectively. Conclusions: FFF beams can be used effectively to treat breast patients. Partial breast techniques or prone breast patients can be treated with a combination of FFF and flattened beams alone. Supine patients require additional small subfields to produce an acceptable plan. Supported in part by Varian Medical Systems.